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The first asymmetric synthesis of the gossypol backbone via a stereocontrolled oxazoline mediated 2,2′ Ullmann coupling has been achieved.

Simple acidic hydrolysis of epoxyamides 4 , derived from 1-tetralones, furnishes the corresponding 2-tetralones in good yield.

A method has been developed by alkylation of chiral lithioformamidines to construct protoberberine alkaloids with a C(9) and C(10) D-ring substitution pattern. This ring pattern was established using an ortho-substituted hydroxymethylbenzene electrophile protected as a silyl ether to ultimately provide (-)-tetrahydropalmatine in 88% ee. Additionally, we have discovered limitations with ortho-substituted electrophiles in the asymmetric formamidine alkylation. These electrophiles have the potential to disrupt the lithium formamidine chelate and cause the selectivity in the alkylation to be uncharacteristically low. The total synthesis of (+/-)-canadine and (-)-tetrahydropalmatine along with the limitations to the formamidine alkylation technology are delineated herein.

Double diastereoselectivity data were analyzed to provide insight into the structural features that influence π-facial selectivity in 1,3-dipolar cycloadditions of chiral and achiral azomethine ylides to chiral, unsaturated bicyclic lactams. Three major steric contributions to the differences in stability (ΔΔG⧧) between competing cycloaddition transition states were identified. The first major set of steric interactions involve that between the dipoles and the substituents on the left hemisphere (R2) and concave faces of the bicyclic lactams. This effectively hindered both α- and β-approaches in the nonextended transition states shown in Figure 1. The second major steric interaction was provided by the nonbonded interactions (i) between the R1 angular substituent on the bicyclic lactam and the π-system of the dipole as shown in Figures 3 and 4. This interaction was shown to be very significant, causing reversal in π-facial attack of chiral and achiral dipoles when the angular substituent is changed from p...

Optically active tricyclic oxazolidine lactams 10 have been prepared using two different routes (Scheme 1). They can be obtained by acid-mediated intramolecular cyclization of bicyclic lactams 13via their acyliminium intermediates producing appended five-, six-, and seven-membered tricyclic systems. Alternatively, 10 can be prepared by cyclocondensation of chiral amino alcohols with cyclopentane-1,2-dicarboxylic acids 12 to give the imide which is reduced or alkylated to the amino alcohols and cyclized to a diastereoisomer mixture of 10. Alkylation of 10 (R″ = H) via its enolate gives stereospecifically α-quaternary products 10 (R″ = alkyl). Degradation of the latter with MeLi or Red-Al® followed by mild acid hydrolysis and aldol cyclization produces the bicyclic ketones 14 and 15 as 1:1 mixtures, readily separated and isolated in > 99% ee. This sequence produced a known non-racemic intermediate 69 for the synthesis of (−)-isocomene.

The reduction of S-(+)-serine methyl ester silyl ether with NaBH 4 followed by acidic workup produced the chiral serinol derivatives with minimum racemization. Addition of MeMgBr gave the functionalized amine diol in high yield with no racemization.

An unsymmetrical biaryl coupling between the Grignard of N-benzyl-7-bromoindoline 25 and the appropriately substituted (o-methoxyaryl)oxazoline 15 leads to an intermediate biaryl which can be elaborated in one step to the 1H-pyrrolo[3,2,1-de]phenanthridine ring system. This simple two-step sequence provides general access to the pyrrolophenanthridine alkaloids 2−6.

Using a modification of the Kharasch−Sosnovsky reaction, the oxidation of oxazolines and thiazolines bearing a variety of 2-alkyl substituents (chiral and achiral) were smoothly oxidized to their corresponding oxazoles and thiazoles, respectively. The key feature involved in the successful implementation of this important oxidation was the use of a mixture of Cu(I) and Cu(II) salts to enhance the oxidation of the intermediate captodative radical, 24. The main limitation of this method was shown when the oxidation failed with oxazolines/thiazolines lacking the carboalkoxy group at C-4.

Further examination of the titled compound has shown that deprotonation of benzylic and allylic carbons are unexpectedly different than those observed with conventional lithium bases.

Bicyclic Lactam 2 was transformed into α-cyanoenamine 8 in a four-step, high-yielding process. γ-Metalation of 8 was achieved using LiTMP in THF/HMPA, and the resultant homoenolate equivalent underwent stereoselective alkylation and subsequent hydrolysis to provide lactams of type 10 as a single diastereomer. Partial reduction and hydrolysis of lactams 10 furnished enantiopure 5-substituted cyclohexenones 13 in good overall yield.

The first asymmetric total synthesis of (S)-(+)-gossypol is described using chiral oxazolines as the naphthyl substituent in a highly diastereoselective aryl–aryl coupling.

Les pyrrolidines 3,4-disubstituees sont obtenues avec de bons rendements a partir de lactames tricycliques qui proviennent d'une cycloaddition dipolaire [3+2] asymetrique d'ylures d'azomethines sur des lactames bicycliques chiraux. Ainsi le traitement des adduits tricycliques 14 ou 17 par le MeLi conduit respectivement aux hydroxylactames N-substitues 16 ou 18 par abstraction du proton benzylique suivie d'un processus anionique de retrocyclisation. Par ailleurs, le traitement de 14 ou 18 par le calcium metallique dans l'ammoniac liquide conduit respectivement aux hydroxylactames bicycliques non substitues 60 ou 56. Par l'intermediaire de ces hydroxylactames bicycliques des exemples significatifs de synthese de pyrrolidines 3,4-disubstituees mono- et bicycliques ont ete obtenus aisement.

The use of chiral bicyclic lactams, in their thiocarbonyl form 9, has been shown to serve as important intermediates for producing α-quaternary alkyl derivatives 8, which were readily transformed into the title compound (−)-1. The reversibility of the thio-Claisen rearrangement, 15⇌8, was clearly demonstrated and appears to be unprecedented. Solvent effects to alter the equilibrium position were studied and found to have only a moderate, but beneficial effect. The title compound was obtained in 14% overall yield in 10 steps from bicyclic lactam, 9.

Ethoxyvinyllithium (EVL) adds cleanly to unsaturated oxazolines, which upon hydrolytic work-up afford the corresponding ketones in high yields and excellent diastereoselectivity.

Allyldimethyltritylsilane (ADTS, 1) has been employed to access a variety of cyclopentanols via Lewis acid mediated annulation to electron deficient olefins. The intermediate silylcyclopentanes were converted to their respective cyclopentanols under mild, nonepimerizing oxidative conditions. In addition, ADTS undergoes efficient annulation onto aldehydes to provide oxetanes and tetrahydrofurans. Some preliminary investigations of this annulation to chiral nonracemic bicyclic lactams are presented.

Using chiral bicyclic lactams, containing an α,β-unsaturation, the key precursor of (−)-indolizomycin was obtained in optically pure form. The sequence involved a > 20:1 diastereoselective cyclopropanation of the unsaturated lactam 5 employing sulfoxonium methylide. TiCl 4 mediated addition of allyltrimethylsilane afforded pyrrolidone 7 in a diastereomeric ratio of > 20:1. The appropriately substituted pyrrolidone 2 was prepared by debenzylation and subsequent alkylation with 3-bromoproponic ester. The six step sequence from commercially available starting materials was performed in 26% overall yield.

A novel asymmetric oxazoline ketenimine rearrangement has been observed to construct α-quaternary substituted ketones. Levels of asymmetric induction in the ketones, of up to 87% ee, were observed for this unusual rearrangement.

Sequential allylation of chiral, nonracemic thiolactam 8 affords clean thio-Claisen [3,3] products 11. The stereoselectivity of the rearrangement was found to be on the order of 10−11:1, with the exo-endo products responsible for the mixture. Addition of hydride or methyllithium−cerium chloride gave clean addition to the thiolactam in the form of its iminium salts 12. Hydrolysis gave 4,4-dialkylcyclohexenones 15, which were cyclized to the cyclopentene derivatives 16 using Grubbs' catalyst.

By employing the appropriate chiral bicyclic lactams, the asymmetric total synthesis of four enantiopure azasugars mentioned in the title were successfully achieved. A series of diastereoselective oxidations ( OsO 4 NMO ) followed by diastereoselective reductions (BH3, 9-BBN) gave good yields of the trisubstituted (16) and tetrasubstituted (2,3,4) pyrrolidine and piperidines respectively.

Enantiomerically pure cis -2,4-disubstituted piperidines were synthesized from chiral thiolactam 2 in six steps via a highly diastereoselective homoenolate alkylation which set the stereochemistry at the C4 carbon. In addition, two cleavage methods were used to cleave the lactam to the desired piperidines with a high level of diastereoselection at the newly created C2 stereocenter.

A remote steric effect in the bicyclic lactam oxazolidine ring has been shown to affect the stereochemical outcome in the thio-Claisen rearrangement taking place in the piperidone ring.

Pd, Ni, and Lewis acid catalyzed rearrangements occur under milder conditions than the thermal version of the titled rearrangements.

The stereocontrolled synthesis of the monomeric subunit of the macrolide dimer disorazole C 1 ( 1 ) has been accomplished by convergent coupling of 3 and 4 using the Stille method.

The enantioselective synthesis of (+)-euphococcinine (1), a homotropane alkaloid, has been achieved in five steps from bicyclic lactam 5.

Cyclobutannulation of the bicyclic lactam with allyldimethyltritylsilane is accomplished in high yield with good diastereoselectivity. The resulting tricyclic system is converted to a enantiomerically pure cyclobutane-fused pyrrolidine.

A second generation approach toward the synthesis of viridenomycin is described. Three key fragments of the molecule have been synthesized in stereochemically pure form. Initial studies toward the coupling of these fragments with the aim of assembling the macrocycle are detailed. Final efforts to reach the title compound are documented.

A study and application of a sequential 1,5 O→O silyl migration/Horner–Wadsworth–Emmons reaction is presented.

Cycloaddition of various sulfur ylides to the chiral unsaturated lactams 1a, 1b led to cyclopropanated products containing a monosubstituted appendage. The stereochemical outcome is such that all the products are mainly (or exclusively) the kinetically controlled endo-syn-8, -9, or endo-anti-10. The latter occurs by virtue of an epimerization to the thermodynamically favored product. Removal of the chiral auxiliary following Wittig reaction on the intermediate carbinol amines (11, 15) gave chiral, nonracemic 1,2,3-trisubstituted cyclopropanes containing various functionalities (13, 16)

The asymmetric synthesis of (S)-(+)-cryptaustoline was accomplished and found to differ in sign of rotation with the natural «S»-(-)-material. The previously assigned absolute configuration was found to be incorrect and is now corrected. The reversal in stereochemistry came about through an unusual manner involving (S)-(+)-laudanosoline (3) cyclizing to (R)-(-)-cryptaustoline ((-)-1c). The mechanism was explored by oxidation of a series of deuterio derivatives of laudanosoline, all of which retained deuterium in the resultant cryptaustoline

Attachment of the chiral formamidine moiety to 6-methoxy-1,2,3,4-tetrahydroisoquinoline afforded the key chiral, nonracemic precursor 8, upon which the azasteroid skeleton was constructed. Asymmetric alkylation with α-halo esters or β-halo ethers gave 15 and 22, respectively, in high ee's. Cyclization, following enamine formation with cyclopentanedione or cyclopentanone, led to the chiral steroidal skeletons 6 and 5, respectively

A series of synthetic manipulations on the naphthalene nucleus, containing a 1-(2-oxazolinyl) moiety, is described. Nucleophilic additions afford both regio- and stereoselective products in the 1- and 4-positions. The latter is oxidatively transformed in the 4-keto system 4 which can undergo various substitutions as well as carbonyl transpostions

The trans-2,3-disubstituted pyrrolidine moiety, found in the pyrrolizidine alkaloids as well as other natural product, has been accessed from the α,β-unsaturated bicyclic lactams 1d and 10. Conjugate addition of lower order cyanocuprates to lactams 1d and 10 resulted in endo entry of the cuprate with high diasterelectivity. Other cuprates were investigated and resulted in diminished or opposite stereoselectivities. Further transformation of the β-subtituted lactams provided the title compounds in good overall yield and high enantiomeric excess

o-Chloro-β-phenethylamines, transformed into the N-tert-butylformamidines, were found to be excellent precursors to indolines following benzyne formation. A series of methoxy-substituted o-chlorophenethylamines containing an N-alkyl or aryl substitutent were subjected to sec-butyllithium producing the ortho-lithiated aromatic which subsequently lost lithium chloride at temperatures ranging from -78 to -50 o C. The resulting benzyne was intramolecularly trapped providing the titled heterocycles. Quenching the reaction resulted in elimination of the tert-butyl isocyanide (isolated after aqueous workup as tert-butylformamide)